Composition for oral administration of tamsulosin hydrochloride and controlled release granule formulation comprising same

ABSTRACT

A composition for oral administration of tamsulosin hydrochloride and a controlled release granule formulation comprising the same exhibited excellent stability and sustained release characteristics of tamsulosin hydrochloride regardless of pH changes for an extended period of time.

FIELD OF THE INVENTION

The present invention relates to a composition for oral administrationof tamsulosin hydrochloride, which exhibits an excellent stability and asustained release of tamsulosin hydrochloride, and a controlled releasegranule formulation comprising the same.

DESCRIPTION OF THE PRIOR ART

Tamsulosin hydrochloride are currently available for treating benignprostatic hypertrophy, and there have been made many attempts to developa controlled release formulation of tamsulosin hydrochloride having goodstability and an extended release rate. For example, European PatentPublication No. 80341A discloses an oral formulation for controlledrelease of tamsulosin which contains multiple drug preparations; andKorean Patent Publication No. 1993-7245 discloses a controlled releaseformulation for oral use comprising the drug, an aggregate-forming agentsuch as cellulose, chitin and chitosan, and an insoluble polymer.However the stability and the release characteristics of theseformulations fluctuate unsatisfactorily depending on the retained foodor pH changes in the gastroenteric organs.

The present inventors have endeavored to develop a composition havinggood stability and sustained release characteristics of tamsulosinhydrochloride under any digestive conditions; and have unexpectedlyfound that a composition comprising tamsulosin hydrochloride, polyvinylacetate and a water-soluble hydroxypropylmethylcellulose is particularlysuitable for oral administration.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the present invention to providea novel tamsulosin hydrochloride composition which exhibits highstability and satisfactory sustained release characteristics oftamsulosin hydrochloride upon oral administration.

It is another object of the present invention to provide a controlledrelease granule formulation comprising said composition.

In accordance with one aspect of the present invention, there isprovided a composition for oral administration of tamsulosinhydrochloride comprising tamsulosin hydrochloride, polyvinylacetate, anda water-soluble hydroxypropylmethylcellulose.

In accordance with another aspect of the present invention, there isprovided a sustained release granule of tamsulosin hydrochloridecomprising tamsulosin hydrochloride, polyvinylacetate, a water-solublehydroxypropylmethylcellulose, and a granulating agent.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and features of the present invention willbecome apparent from the following description of the invention, whentaken in conjunction with the accompanying drawings, which respectivelyshow:

FIG. 1: Dissolution profiles of tamsulosin hydrochloride observed forthe hard capsule prepared in Example 17 and Harnal capsule (Jeil Pharm.,Korea);

FIGS. 2A and 2B: Dissolution profiles of tamsulosin hydrochlorideobserved for the hard capsule prepared in Example 17 (A) and Harmalcapsule (B) after storage for 10 days under the condition of TestExample 2; and

FIGS. 3A and 3B: Microscopic photographs of the coated granule preparedin Example 15 (A) and the granule of Harnal capsule (B).

DETAILED DESCRIPTION OF THE INVENTION

The composition of the present invention comprises tamsulosinhydrochloride, polyvinylacetate, and a water-solublehydroxypropylcellulose.

The inventive composition may further comprise various granulatingagents, coating materials, and pharmaceutically acceptable additives.

Each ingredient of the inventive composition and granule formulation isdescribed in detail as follows.

Tamsulosin Hydrochloride

Tamsulosin hydrochloride, the active ingredient of the inventivecomposition, has a low water-solubility. A typical daily do oftamsulosin hydrochloride in case of treating urination disorderaccompanying benign prostatic hypertrophy ranges from 0.2 to 0.8 mg, andit should be administered once a day 30 min before a meal. However, itshould be understood that the dosage of tamsulosin hydrochloride shouldbe determined in light of various relevant factors including thecondition to be treated, the severity of the patient's symptoms, theroute of administration, or the physiological form of the anticanceragent; and therefore, the dosage suggested above should not be construedto limit the scope of the invention in anyway.

Polyvinylacetate

Polyvinylacetate plays an important role in assisting granulating agentin the process of forming granules and maintaining pores formed in thegranules for some period of time after the inventive granule formulationis dissolved in an aqueous medium. Consequently, polyvinylacetateconfers on the composition of the inventive composition with sustainedrelease capability of the active ingredient for an extended period oftime regardless of pH of the aqueous medium.

In the inventive composition, polyvinylacetate may be used alone or inthe form of a mixture with other pharmaceutically acceptable materials,preferably in the form of a powder or a suspension containing more than30% by weight or more of polyvinylacetate.

For example, Kollidon SR® (BASF), a powder prepared by mixingpolyvinylacetate and polyvinylpyrrolidone at a ratio of 8:2 (w/w) andspray-drying the mixture, and Kollicoat SR30D® (solid content: 30%,BASF), a suspension (or a diluted aqueous solution) prepared by mixingpolyvinylacetate, polyvinylpyrrolidone and sodium lauryl sulfate, andsuspending the mixture in water, may be used in the present invention asa source of polyvinylacetate. In addition, any pharmaceuticallyacceptable material may be used as a source of polyvinylacetate insofaras it contains 30% by weight or more of polyvinylacetate.

Polyvinylacetate may be employed in the inventive composition in anamount ranging from 20 to 1000 parts by weight, preferably 40 to 600parts by weight, more preferably 50 to 300 parts by weight based on 1part by weight of tamsulosin hydrochloride.

Water-Soluble Hydroxypropylmethylcellulose

A water-soluble hydroxypropylmethylcellulose (HPMC) controls theinitial-phase release of the active ingredient by forming pores, throughwhich the active ingredient is released. In order to obtain a desiredsustained release pattern, it is preferable to employ a water-solubleHPMC having a high viscosity, and the desired effect may not be achievedwhen a low-viscosity water-soluble HPMC is employed. Therefore, thewater-soluble HPMC having a high viscosity of more than 10,000 cps,preferably 15,000 to 100,000 cps, is used in the present invention, andrepresentative examples thereof include METOLOSE 60SH, 65SH and 90SH(Shin-Etsu).

The water-soluble HPMC may be used in an amount ranging from 0.1 to 500parts by weight, preferably 1 to 100 parts by weight, more preferably 2to 50 parts by weight based on 1 part by weight of tamsulosinhydrochloride.

A controlled release granule formulation prepared by using the inventivecomposition may further comprise the following ingredients.

Granulating Agent

The inventive granule formulation may comprise a granulating agent andexamples thereof include microcrystalline cellulose, lactose andinorganic carrier such as dibasic calcium phosphate, dibasic calciumphosphate dihydrate and tribasic calcium phosphate, whereinmicrocrystalline cellulose and dibasic calcium phosphate (e.g. A-Tab®,Rhodia) are preferred.

The granulating agent may be used in an amount ranging from 1 to 2000parts by weight, preferably 10 to 1000 parts by weight based on 1 partby weight of tamsulosin hydrochloride.

Coating Material

The inventive granule formulation of tamsulosin hydrochloride mayfurther be coated with a conventional enteric coating material or apolymeric coating material for the purpose of precisely controlling theabsorption of the active ingredient in the gastrointestinal treat.

Examples of the enteric coating material includehydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, polyvinylacetate phthalate, cellulose acetatephthalate, shellac, methacrylate-methylmethacrylate copolymer andmethacrylate-ethylacrylate copolymer. Examples of the polymeric coatingmaterial include hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, polyvinylacetate and a mixture thereof.

The coating material may be employed in an amount ranging from 0.2 to100 parts by weight, preferably 1 to 50 parts by weight based on theamount 1 part by weight of tamsulosin hydrochloride.

Pharmaceutically Acceptable Additives

The inventive granule formulation may further comprise conventionalpharmaceutically acceptable additives for preparing it into variousformulations, and exemplary pharmaceutically acceptable additive includea conventional plasticizer, lubricant and other aid.

The pharmaceutical acceptable additive may be employed in an amountranging from 0.1 to 500 parts by weight, preferably 1 to 200 parts byweight, more preferably 2 to 50 parts by weight based on 1 part byweight of tamsulosin hydrochloride.

The inventive composition of tamsulosin hydrochloride may be formulatedinto a granule formulation by a conventional method comprising the stepsof (i) mixing the composition with a granulating agent, and (ii)subjecting the mixture to wet grinding, compression molding andspheronizing to obtain a wet granule. The granule may be further coatedwith a coating material dissolved in water to obtain a coated granule.If necessary, the granule may be further mixed with pharmaceuticalacceptable additives and filled into a hard gelatin capsule to obtain acapsule formulation.

The following Examples are intended to further illustrate the presentinvention without limiting its scope.

I. Preparation of Controlled Release Granule Formulation of TamsulosinHydrochloride

EXAMPLE 1

0.2 part by weight of tamsulosin hydrochloride, 21.0 parts by weight ofKollicoat SR30D (BASF, polyvinylacetate), 5.5 parts by weight ofMETOLOSE 90SH (water-soluble HPMC; viscosity: 100,000 cps), and 123.5parts by weight of micro crystalline cellulose (granulating agent) wereplaced in a high speed mixer, and an appropriate amount of water wasadded thereto. The mixture was mixed for 10 to 15 min and treated with awet grinder obtain a ground material, which was passed through acompression mold equipped with a 0.8 mm mesh, and granulated with asheronizer to obtain a desired granule.

EXAMPLE 2

The procedure of Example 1 was repeated except for using 133.5 parts byweight of dibasic calcium phosphate as a granulating agent, to obtain adesired granule.

EXAMPLE 3

The procedure of Example 1 was repeated except for using 95.5 parts byweight of dibasic calcium phosphate dihydrate as a granulating agent, toobtain a desired granule.

EXAMPLE 4

The procedure of Example 1 was repeated except for using 128.5 parts byweight of lactose as a granulating agent, to obtain a desired granule.

EXAMPLE 5

The procedure of Example 1 was repeated except for using a mixture of 60parts by weight of lactose and 68.5 parts by weight of microcrystallinecellulose as a granulating agent, to obtain a desired granule.

EXAMPLE 6

The procedure of Example 1 was repeated except for using 3.8 parts byweight of METOLOSE 65SH (viscosity: 4,000 cps) instead of METOLOSE 90SH,to obtain a desired granule.

EXAMPLE 7

The procedure of Example 1 was repeated except for using 4.5 parts byweight of METOLOSE 65SH instead of METOLOSE 90SH, to obtain a desiredgranule.

EXAMPLE 8

The procedure of Example 1 was repeated except for using 70.0 parts byweight of Kollidon SR instead of Kollicoat SR30D, and 34.5 parts byweight of METOLOSE 65SH instead of METOLOSE 90SH, to obtain a desiredgranule.

EXAMPLE 9

The procedure of Example 1 was repeated except for using 78.0 parts byweight of Kollidon SR instead of Kollicoat SR30D, and 55.5 parts byweight of microcrystalline cellulose instead of 123.5 parts by weight,obtain a desired granule.

II. Preparation of Coated-Controlled Release Granule of TamsulosinHydrochloride

EXAMPLE 10

150.0 parts by weight of the controlled release granule of tamsulosinhydrochloride obtained in Example 1 was placed in NQ-160 fluidized bed(DALTON) and bottom-sprayed with a coating solution comprising 9.7 partsby weight of Kollicoat SR30D (solid content: 2.9 parts by weight, acoating material), a mixture of 0.56 part by weight ofpolyvinylpyrrolidone and 0.43 part by weight of propyleneglycol (aplasticizer), and 18.0 parts by weight of distilled water, to obtain adesired coated granule. During the coating, the entrance temperature was36 to 39° C., exit temperature was 26 to 28° C., the rate of injectionof the coating solution was 0.7 to 0.8 ml /min, and the spraying airpressure was 45 to 55 psi.

EXAMPLE 11

The procedure of Example 10 was repeated except for using 3.4 parts byweight of ethylcellulose (IPI) and 7.6 parts by weight ofhydroxypropylmethylcellulose (Shin-Etsu) as a coating material, toobtain a desired coated granule.

EXAMPLE 12

The procedure of Example 10 was repeated except for using a coatingsolution comprising 12.0 parts by weight of Eudragit L30D-55(methacrylate-ethylacrylate copolymer, solid content: 3.6 parts byweight, Roehm) as a coating material, 0.54 part by weight of triacetineas a plasticizer and 21.8 parts by weight of water in place of thecoating solution of Example 10, to obtain a desired coated granule.

EXAMPLE 13

The procedure of Example 10 was repeated except for using 4.0 parts byweight of hydroxypropylmethylcellulose phthalate (solid content: 3.6parts by weight, Roehm) as a coating material, to obtain a desiredcoated granule.

EXAMPLE 14

The procedure of Example 10 was repeated except for using 9.0 parts byweight of Eudragit E-100 (methacrylate-methylmethacrylate copolymer,solid content: 3.6 parts by weight, Roehm) as a coating material, toobtain a desired coated granule.

EXAMPLE 15

The procedure of Example 10 was repeated except for using 153.9 parts byweight of the coated-granule obtained in Example 10 instead of thegranule obtained in Example 1, and a coating solution comprising 12.0parts by weight of Eudragit L30D-55 (methacrylate-ethylacrylatecopolymer, solid content: 3.6 parts by weight, Roehm) as a coatingmaterial, 0.54 part by weight of triacetine as a plasticizer and 21.8parts by weight of water in place of the coating solution of Example 10,to obtain a desired coated granule.

III. Preparation of Hard Capsule Comprising Controlled Release Granuleof Tamsulosine Hydrochloride

EXAMPLE 16

158.14 parts by weight of the coated granule obtained in Example 13, 0.5part by weight of talc, and 0.5 part by weight of calcium stearate weremixed, and a hard capsule was filled with the mixture to obtain adesired hard capsule.

EXAMPLE 17

158.14 parts by weight of the coated granule obtained in Example 15, 0.5part by weight of talc, and 0.5 part by weight of calcium stearate weremixed, and a hard capsule was filled with the mixture to obtain adesired hard capsule.

TEST EXAMPLE 1 Dissolution Test

A dissolution test for tamsulosin hydrochloride was conducted using thecapsule obtained in Example 17 and Hamal (Jeil Pharm.) capsule as acomparative preparation as follows.

500 ml of artificial gastric juice (pH 1.2) containing 1 ml of Tween 80was used as test solution (1). Each treat capsule was added to testsolution (1), the mixture was agitated at 37±0.5° C. and 100 rpm for 2hours, and a 10 ml sample was taken from the test solution (1). Then,the test solution (1) was changed with test solution (2), 500 ml of aphosphate buffer (pH 7.2), the same agitating procedure was repeated,and 10 ml samples were taken from the test solution (2) at hour 1 and 3after the start of the agitation, respectively. The sample taken fromthe test solution (1) was mixed with 2.0 ml of an internal standard(propyl parahydroxybenzoate dissolved in a mixture ofwater:acetonitrile=7:3), while each of the samples taken from the testsolution (2) was mixed with a mixture of 0.5 N HCl and 2.0 ml of theinternal standard. The resulting mixture was filtered through a 0.5 μmmembrane filter, and subjected to liquid chromatography (column:Cosmosil (ODS) (4.6×150 mm, 5 μm) C₁₈; temperature: 40° C.; mobilephase: aqueous HClO₄ (adjusted to pH 2.0 using NaOH):acetonitrile=7:3;flow rate: 1.0 ml/min; injection volume: 500 μl; and wave length: 225nm) to analyze the time-dependent released amount of tamsulosinhydrochloride. The results are shown in FIG. 1.

As shown in FIG. 1, the capsule of the present invention and Harnalcapsule exhibited similar tamsulosin hydrochloride release patternsregardless of the pH.

TEST EXAMPLE 2 Stability Test

12 of the hard capsules obtained in Example 17 and 12 of Harnal capsule(Jeil Pharm.) were each placed into a HDPE bottle. Then, the bottle wassealed, and kept at 60° C., or at 40° C. and 75% relative humidity (astress condition).

At days 0, 10 or 30 of in such treatment, each residual percentage oftamsulosin hydrochloride in the inventive or Harnal capsule was analyzedusing a liquid chromatography, and the results is listed in Table I.TABLE I 0 day 10 days 30 days Example 17 100 ± 1.75% 98.7 ± 1.36% 93.5 ±3.98% Harnal 100 ± 3.43% 98.6 ± 0.0%  91.0 ± 3.34%

Further, using the inventive and Harnal capsules kepted for 10 daysunder the above stress condition, the procedure of Test Example 1 wasrepeated. The results are shown in FIGS. 2A (the inventive capsule) and2B (Harnal capsule).

As the results show, the inventive capsule of tamsulosin hydrochlorideexhibited high stability and good sustained release characteristics oftamsulosin hydrochloride, comparable to Harnal capsule.

TEST EXAMPLE 3 Sphericity Test

10-granule particles of the coated granule obtained in Example 15 andthose of Harnal capsule were each examined using a microscope (NikkonSMZ800). On each microscopic photograph, a least circumscribed circle ofthe granule was drawn, and the distance from the circumcenter andsurface of the granule was measured to obtain the minimum distance (A)and maximum distance (B). The sphericity of each granule was evaluatedby A/B, and the results are listed in Table II. TABLE II Granule No. 1 23 4 5 6 7 8 9 10 Average Deviation Example 0.96 0.93 0.89 0.89 0.91 0.860.87 0.83 0.88 0.83 0.89 0.04 15 Harnal 0.80 0.80 0.88 0.92 0.65 0.810.78 0.88 0.80 0.63 0.79 0.10

The results in Table II suggest that the granule of the presentinvention is more spherical than the granule of Harnal, for the averageA/B of the inventive granule was closer to 1 than the comparativegranule. Thus, composition of the present invention is capable offorming uniform granules.

As can be seen from the above, the inventive composition for oraladministration of tamsulosin hydrochloride having high stability, a goodsustained release rate of the active ingredient and the capability forforming uniform granules can be advantageously used in various fieldsincluding medical science and pharmaceutical chemistry.

While the invention has been described with respect to the specificembodiments, it should be recognized that various modifications andchanges may be made by those skilled in the art to the invention whichalso fall within the scope of the invention as defined by the appendedclaims.

1. A composition for oral administration of tamsulosin hydrochloridecomprising tamsulosin hydrochloride, polyvinylacetate, and awater-soluble hydroxypropylmethylcellulose.
 2. The composition of claim1, wherein polyvinylacetate is in the form of a powder or suspensioncomprising polyvinylacetate and a pharmaceutically acceptable additive.3. The composition of claim 1, wherein the amount of polyvinylacetateranges from 20 to 1000 parts by weight based on 1 part by weight oftamsulosin hydrochloride.
 4. The composition of claim 1, wherein thewater-soluble hydroxypropylmethylcellulose has a viscosity ranging from10,000 to 100,000 cps.
 5. The composition of claim 1, wherein the amountof water-soluble hydroxypropylmethylcellulose ranges from 0.1 to 500parts by weight based on 1 part by weight of tamsulosin hydrochloride.6. A sustained release granule of tamsulosin hydrochloride comprisingtamsulosin hydrochloride, polyvinylacetate, a water-solublehydroxypropylmethylcellulose, and a granulating agent.
 7. The granule ofclaim 6, wherein the granulating agent is selected from the groupconsisting of lactose, microcrystalline cellulose, dibasic calciumphosphate, dibasic calcium phosphate dihydrate, tribasic calciumphosphate and a mixture thereof.
 8. The granule of claim 6, wherein theamount of the granulating agent ranges from 1 to 2000 parts by weightbased on 1 part by weight of tamsulosin hydrochloride.
 9. The granule ofclaim 6, which is coated with a coating material.
 10. The granule ofclaim 9, wherein the coating material is a polymeric or an entericcoating material.
 11. The granule of claim 9, wherein the amount of thecoating material ranges from 0.2 to 100 parts by weight based on 1 partby weight of tamsulosin hydrochloride.